DOCSLIB.ORG

Tratamiento Farmacológico Contra La Obesidad

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tratamiento Farmacológico Contra La Obesidad Rev. Colomb. Cienc. Quím. Farm., Vol. 41 (2), 217-261, 2012 www.farmacia.unal.edu.co Artículo de revisión Tratamiento farmacológico contra la obesidad Milton Enrique Londoño-Lemos Departamento de Química Inorgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, México, D. F. 04510, México. Correo electrónico: [email protected]. Recibido para evaluación: 23 de noviembre de 2012. Aceptado para publicación: 20 de diciembre de 2012. Resumen La obesidad, una de las enfermedades más críticas del siglo XXI, se halla asociada con otros problemas de salud como la diabetes tipo 2, las enfermedades cardiovasculares y una expectativa de vida reducida, y ejerce un efecto importante sobre la economía. Pese a que se han desarrollado fármacos antiobesidad que actúan de diferentes maneras (disminuyendo el apetito, alterando el metabolismo o inhibiendo la absor- ción calórica), dichos fármacos han representado serias preocupaciones en cuanto a la seguridad en su uso, a tal punto que, debido a sus efectos secundarios, Se retiraron del mercado la sibutramina y el rimonabant; a consecuencia de estos reveses existen pocos medicamentos antiobesidad aceptados. Por otra parte, el conocimiento acerca del eje intestino-cerebro ayuda a entender cómo funciona el sistema gastroentero- pancreático, con relación a una serie de péptidos y hormonas que participan en la regulación alimentaria y el cerebro, específicamente el hipotálamo como centro homeostático de los estados de hambre y anorexia, o del apetito, y por ende, del peso corporal. Esto nos lleva a estudiar aquellos fármacos que se encuentran en fase de investigación y desarrollo como las monoterapias y las combinaciones, para concluir que existen tres fármacos aprobados por la Agencia de Alimentos y Medicamentos (FDA, por sus siglas en inglés), dos de ellos recientemente (en el 2012), y otros que podrían llegar a ser aceptados para su uso terapéutico. Palabras clave: obesidad, intestino-cerebro, farmacoterapia, mecanismos de acción. Pharmacotherapy for obesity 217 Londoño-Lemos Summary Obesity is one of the most critical diseases of the 21st century, which is associ- ated with other health problems such as type 2 diabetes, cardiovascular disease and reduced life expectancy, and a strong effect on the economy. Over time, have developed anti-obesity drugs which work in different ways: by suppressing appe- tite, altering metabolism or inhibiting absorption heat. However, these drugs have had serious concerns about the safety of commonly prescribed use derivative side effects, leading the recent withdrawal of sibutramine and rimonabant. As a result of these setbacks, there are few anti-obesity drugs accepted. Knowledge about the gut-brain axis help you understand how the gastro-entero pancreatic, related to a series of peptides and hormones involved in food regulation and the brain, specifi- cally the hypothalamus as a central regulator of the states of hunger and anorexia or appetite and body weight thereby. These lead us to study those drugs that are under research and development as monotherapies and combinations to conclude that there are three drugs already approved by the Food and Drug Administration or by its acronym U.S. FDA (two of them recently approved in 2012) and others which will become accepted for therapeutic use. Keywords: Obesity, gut-brain, pharmacotherapy, mechanisms of action. Tratamiento farmacológico contra la obesidad En la mayoría de las sociedades la prevalencia de la obesidad ha alcanzado proporciones epidémicas (1). Por ejemplo, Estados Unidos es el segundo país con obesidad a nivel mundial, ya que el 80,5% de los adultos presentan sobrepeso u obesidad. De acuerdo con las predicciones del Gobierno, se estima que el 75% de adultos y cerca de un 24% de los niños y adolescentes en Estados Unidos tendrán obesidad o sobrepeso en el 2015 (2). Hoy en día la obesidad es definida como una enfermedad neurobiológica que reduce la esperanza de vida y es un factor de riesgo para desarrollar enfermedades cardiovasculares, ciertos tipos de cánceres y desarrollo de diabetes tipo 2 (3). Por eso la obesidad es considerada un problema de salud pública, que afecta a otros sectores sociales como el industrial, el educativo y el gubernamental, además de generar costos de millones de dólares a la economía. 218 Tratamiento farmacológico contra la obesidad En estudios recientes, científicos de la Universidad de Liverpool argumentaron que los fármacos antiobesidad no tienen ventajas duraderas para la salud y el bienestar por- que solo tratan las consecuencias biológicas de la obesidad y no las causas psicológi- cas importantes del sobreconsumo y la ganancia de peso. De hecho, el doctor Jason Halford, líder en obesidad y apetito, de la Universidad de Liverpool, precisa que los fabricantes de medicamentos antiobesidad se enfocan sobre todo en la pérdida de peso como su principal objetivo y no toman en cuenta los factores motivacionales y comportamientos mentales que comúnmente causan la obesidad. La obesidad típica resulta de consumir demasiado alimento, combinado con un estilo de vida sedentario; sin embargo, la gente obesa también tiene una relación psicológica complicada con los alimentos, ante los cuales le es difícil controlar el apetito lo suficiente como para manejar su peso corporal. Los fármacos antiobesidad pueden obrar de varias maneras, por ejemplo: suprimiendo el apetito, alterando el metabolismo o inhibiendo la absorción de calorías, pero los comúnmente prescritos han generado serias preocupaciones para la seguridad de los pacientes, a tal punto que recién se han retirado del mercado europeo medicamentos líderes como la sibutramina (reductil, meridia) y el rimonabant (Acomplia). A conse- cuencia de estos reveses, hay pocos medicamentos antiobesidad en desarrollo. El profesor Tim Kirkham, autoridad en el área de la biofísica del apetito en la Univer- sidad de Liverpool, afirma: Los nuevos y efectivos tratamientos antiobesidad deben apuntar hacia diferentes factores. Necesitamos identificar fármacos que puedan selectivamente afectar el deseo de comer, el disfrute de comer, plenitud y satisfacción. Intervenciones dise- ñadas específicamente para modular estos procesos podrían ayudar a reducir la experiencia aversiva de la dieta y maximizar la capacidad de exitosamente ganar peso sobre su apetito. Sabemos poco sobre los efectos comportamentales de los fármacos antiobesidad bajo desarrollo, y así tenemos poca indicación [de] si estos nuevos tratamientos tratan las causas subyacentes de la obesidad (4). Hay que tener en cuenta que la regulación corporal es un sistema complejo de siste- mas de retroalimentación múltiples sobrepuestos. La obesidad resulta por una mayor ingesta de energía que de un gasto energético, aunque este balance es afectado por fac- tores genéticos, ambientales y culturales. Los tres mecanismos primarios que pueden ser alterados para revertir el estado de ingesta energética mayor que el gasto energético son la ingesta de alimento, el manejo de nutrientes y el gasto energético (v. figura 1). Muchos de los medicamentos disponibles y en desarrollo apuntan a uno de estos tres mecanismos: reducir el apetito, decrecer la absorción de nutrientes, incrementar la ter- mogénesis (5). 219 Londoño-Lemos Figura 1. Balance energético entre la ingesta calórica y su gasto respectivo (modificado de la refe- rencia 5). Se debe recordar que la manera más común utilizada para estimar el nivel de obesi- dad que tiene una persona es por medio del índice de masa corporal, IMC (o BMI, por sus siglas en inglés), que define la razón del peso corporal en kilogramos y su altura en metros cuadrados (kg/m2). De acuerdo con este criterio, la Organización Mundial de la Salud (OMS) (6) ha clasificado los diversos estados en los cuales se encuentra una persona (v. figura 2). Figura 2. Valores del índice de masa corporal de acuerdo con el estado de la persona. La OMS estima que en el mundo 1.700 millones de personas presentan sobrepeso y 310 millones son obesas. En la tabla 1 podemos observar las cifras actuales de los países donde más se presenta esta enfermedad, al punto de ser considerada un pro- blema de salud pública. 220 Tratamiento farmacológico contra la obesidad Tabla 1. Tasa de obesidad (> 25 kg/m2) en el mundo, 2010 (%) País Micronesia 93,1 91,1 Estados Unidos de América 80,5 76,7 Argentina 77,7 71,2 Australia 75,7 66,5 Venezuela 74,4 67,3 México 73,6 73,0 Chile 68,4 73,3 Reino Unido 67,8 63,8 Canadá 66,9 59,5 Colombia 62,6 61,1 Fuente: tomado de la referencia 109. Sabemos que hoy en día se considera a la obesidad como una enfermedad crónica, com- pleja, multifactorial, que aún no tiene una cura específica, no está siendo bien enfocada y por ende no es tratada adecuadamente. Aún más preocupante resulta el hecho de que la obesidad aumenta tanto en los países en desarrollo como en los desarrollados (v. figura 3). Figura 3. El sobrepeso va en ascenso de los países menos desarrollados a los más desarrollados (109). 221 Londoño-Lemos Tomando como referencia a nivel latinoamericano a México, según la última Encuesta Nacional de Salud y Nutrición (Ensanut, 2006), el 71,9% de las mujeres mayores de 20 años y el 66,7% de los hombres tienen prevalencia combinada de sobrepeso u obesi- dad. Y causa alarma lo reportado en el 2010 sobre el primer lugar mundial en obesidad infantil que presenta México, según el Instituto Mexicano del Seguro Social (IMSS), por encima de países desarrollados como Estados Unidos. Existe una fuerte correlación entre el desarrollo
Load more

Recommended publications
  • Neuropeptide Y6 Receptors Are Critical Regulators of Energy Metabolism
    NEUROPEPTIDE Y6 RECEPTORS ARE CRITICAL REGULATORS OF ENERGY METABOLISM Ernie Yulyaningsih A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy St Vincent’s Clinical School Faculty of Medicine February 2014 Table of Contents GENERAL INTRODUCTION ....................................................................... 2 Obesity .......................................................................................................... 3 Regulators of energy homeostasis................................................................ 3 Neuropeptide Y ............................................................................................ 4 The Y1 receptor ......................................................................................... 6 The Y2 receptor ......................................................................................... 9 The Y4 receptor ....................................................................................... 16 The Y5 receptor ....................................................................................... 21 The Y6 receptor ....................................................................................... 25 Hypothesis and overall aims of the study .................................................. 28 EXPERIMENTAL PROCEDURES ............................................................. 29 Generation and genotyping of the Y6-/--LacZ mouse ................................ 30 Animal experiments ..................................................................................
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2012/0022039 A1 Schwink Et Al
    US 20120022039A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0022039 A1 Schwink et al. (43) Pub. Date: Jan. 26, 2012 (54) NOVEL SUBSTITUTED INDANES, METHOD Publication Classification FOR THE PRODUCTION THEREOF, AND USE (51) Int. Cl. THEREOF AS DRUGS A 6LX 3L/397 (2006.01) C07D 207/06 (2006.01) C07D 2L/22 (2006.01) C07D 22.3/04 (2006.01) (75) Inventors: Lothar Schwink, Frankfurt am C07D 22L/22 (2006.01) Main (DE); Siegfried Stengelin, C07C 235/54 (2006.01) Frankfurt am Main (DE); Matthias C07D 307/14 (2006.01) Gossel, Frankfurt am Main (DE); A63L/35 (2006.01) Klaus Wirth, Frankfurt am Main A6II 3/40 (2006.01) (DE) A6II 3/445 (2006.01) A6II 3/55 (2006.01) A63L/439 (2006.01) A6II 3/66 (2006.01) (73) Assignee: SANOFI, Paris (FR) A6II 3/34 (2006.01) A6IP3/10 (2006.01) A6IP3/04 (2006.01) A6IP3/06 (2006.01) (21) Appl. No.: 13/201410 A6IPL/I6 (2006.01) A6IP3/00 (2006.01) C07D 309/04 (2006.01) (52) U.S. Cl. .................... 514/210.01; 549/426: 548/578; (22) PCT Filed: Feb. 12, 2010 546/205; 540/484; 546/112:564/176; 549/494; 514/459:514/408: 514/319; 514/212.01; 514/299; 514/622:514/471 (86). PCT No.: PCT/EP2010/051796 (57) ABSTRACT The invention relates to substituted indanes and derivatives S371 (c)(1), thereof, to physiologically acceptable salts and physiologi (2), (4) Date: Oct. 4, 2011 cally functional derivatives thereof, to the production thereof, to drugs containing at least one substituted indane according (30) Foreign Application Priority Data to the invention or derivative thereof, and to the use of the Substituted indanes according to the invention and to deriva Feb.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Instituto Superior De Ciências Da Saúde Egas Moniz
    INSTITUTO SUPERIOR DE CIÊNCIAS DA SAÚDE EGAS MONIZ MESTRADO INTEGRADO EM CIÊNCIAS FARMACÊUTICAS REGULAÇÃO DO COMPORTAMENTO ALIMENTAR E NOVOS ALVOS TERAPÊUTICOS Trabalho submetido por Christelle Sophia Paulino Rodrigues para a obtenção do grau de Mestre em Ciências Farmacêuticas Trabalho orientado por Doutora Véronique Sena Outubro de 2013 Agradecimentos Agradecimentos Embora esta tese seja individual, não poderia deixar de usar este espaço para agradecer quem me apoiou durante esta fase e durante os cinco anos anteriores aquando a minha formação académica. As palavras não são suficientes para descrever o sentimento de agradecimento, mas o sentimento é real e profundo. Em primeiro lugar, gostaria de agradecer o Instituto Superior de Ciências da Saúde Egas Moniz que me forneceu o ensino adequado para me ajudar a cumprir os meus objetivos. À professora Véronique pela presença, pela orientação, pelo tempo de dedicou e pela ajuda que forneceu. Este trabalho não teria existido sem a professora. À Salete e ao Francisco que se disponibilizaram para me ajudar a corrigir a gramática e a ortografia. Ao meus amigos, familiares e colegas, que sempre acreditaram em mim. Ao meu irmão, por ser quem é. Aos meus pais pelo apoio moral, pela dedicação, pelo carinho e pelos sacrifícios que fizeram para eu chegar ao fim desta etapa. Dedico-lhes esta tese por isso, e por tudo o mais que fizeram por mim. A todos, obrigado. 3 Regulação do comportamento alimentar e novo alvos terapêuticos Resumo O comportamento alimentar depende da regulação do equilíbrio entre a ingestão de calorias e o gasto energético. Esta regulação ocorre a nível cerebral onde o hipotálamo exerce um papel fundamental.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Velneperit Item No. 33850 CAS Registry No.: 342577-38-2 Formal Name: trans-4-[[(1,1-dimethylethyl)sulfonyl] F amino]-N-[5-(trifluoromethyl)-2-pyridinyl]- F cyclohexanecarboxamide N F Synonym: S-2367 O MF: C17H24F3N3O3S FW: 407.5 O N Purity: ≥98% S H UV/Vis.: λ: 244, 279 nm N max O Supplied as: A solid H Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Velneperit is supplied as a solid. A stock solution may be made by dissolving the velneperit in the solvent of choice, which should be purged with an inert gas. Velneperit is soluble in the organic solvent DMSO. Description 1 Velneperit is a nonpeptide antagonist of neuropeptide Y (NPY) receptor Y5 (Ki = 5.3 nM). It is selective for Y5 over Y1, Y2, and Y4 receptors, as well as a panel of 44 receptors, ion channels, transporters and enzymes, at 10 µM. Velneperit inhibits NPY-induced decreases in forskolin-induced cAMP production in CHO-K1 cells expressing the human Y5 receptor (IC50 = 169 nM). In vivo, velneperit (50 mg/kg) suppresses Y5 agonist-induced increases in food intake in high-fat diet-induced obese (DIO) mice. It also reduces body weight gain and suppresses food intake in DIO mice. Reference 1. Fukasaka, Y., Nambu, H., Tanioka, H., et al. An insurmountable NPY Y5 receptor antagonist exhibits superior anti-obesity effects in high-fat diet-induced obese mice. Neuropeptides 70, 55-63 (2018). WARNING CAYMAN CHEMICAL THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al
    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.
    [Show full text]
  • Orally Active Compound Library (96-Well)
    • Bioactive Molecules • Building Blocks • Intermediates www.ChemScene.com Orally Active Compound Library (96-well) Product Details: Catalog Number: CS-L061 Formulation: A collection of 2244 orally active compounds supplied as pre-dissolved Solutions or Solid Container: 96- or 384-well Plate with Peelable Foil Seal; 96-well Format Sample Storage Tube With Screw Cap and Optional 2D Barcode Storage: -80°C Shipping: Blue ice Packaging: Inert gas Plate layout: CS-L061-1 1 2 3 4 5 6 7 8 9 10 11 12 a Empty Vonoprazan Mivebresib AZD0156 BAY-876 Tomivosertib PQR620 NPS-2143 R547 PAP-1 Delpazolid Empty Varenicline b Empty Varenicline (Hydrochlorid Varenicline A-205804 CI-1044 KW-8232 GSK583 Quiflapon MRK-016 Diroximel Empty e) (Tartrate) fumarate SHP099 c Empty A 922500 SHP099 (hydrochlorid Nevanimibe Pactimibe Pactimibe GNF-6231 MLi-2 KDM5-IN-1 PACMA 31 Empty e) hydrochloride (sulfate) Rilmenidine d Empty Cadazolid Treprostinil GSK3179106 Esaxerenone (hemifumarat Rilmenidine Fisogatinib BP-1-102 Avadomide Aprepitant Empty e) (phosphate) Cl-amidine AZD5153 (6- e Empty Maropitant Abscisic acid (hydrochlorid BGG463 WNK463 Ticagrelor Axitinib Hydroxy-2- CGS 15943 Pipamperone Empty e) naphthoic Setogepram Teglarinad f Empty Y-27632 GSK2193874 Lanabecestat CXD101 Ritlecitinib YL0919 PCC0208009 (sodium salt) (chloride) Futibatinib Empty TAK-659 g Empty NCB-0846 GS-444217 (hydrochlorid Navitoclax ABX464 Zibotentan Simurosertib (R)- CEP-40783 MK-8617 Empty e) Simurosertib Choline JNJ- h Empty CCT251236 (bitartrate) Sarcosine Brensocatib AS-605240 PF-06840003
    [Show full text]
  • Antiobesity Pharmacotherapy: New Drugs and Emerging Targets
    State of the Art nature publishing group STATE ART Antiobesity Pharmacotherapy: New Drugs and Emerging Targets GW Kim1, JE Lin1, ES Blomain1 and SA Waldman1 Obesity is a growing pandemic, and related health and economic costs are staggering. Pharmacotherapy, partnered with lifestyle modifications, forms the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing antiobesity therapies, including targets, mechanisms, and developmental status, are highlighted. Progress in this field is underscored by Belviq (lorcaserin) and Qsymia (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic weight management in obese patients. On the horizon, novel insights into metabolism and energy homeostasis reveal guanosine 3′,5′-cyclic monophosphate (cGMP) signaling circuits as emerging targets for antiobesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches, leveraging existing approved drugs that modulate cGMP levels for the management of obesity. Obesity is a global public health problem. The obesity epidemic prepared foods vs. fast foods or prepackaged foods in terms has been growing in developed nations, including the United of preservation, portability, and palatability; the marketing of States, for decades.1 Moreover, this epidemic
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • NPY Receptors As Potential Targets for Anti-‐Obesity Drug Development
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Sydney eScholarship Yulyaningsih et al.: Anti-obesity drug development British Journal of Pharmacology, 163(6): 1170-1202 NPY receptors as potential targets for anti-obesity drug development Ernie Yulyaningsih1, Lei Zhang1, Herbert Herzog1,2 and Amanda Sainsbury1,3 1 Neuroscience Research Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Darlinghurst, Sydney, NSW, 2 3 Australia, Faculty of Medicine, University of NSW, Sydney, NSW, Australia, and School of Medical Sciences, University of NSW, Sydney, NSW, Australia Abstract The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review. Abbreviations ARC, arcuate nucleus; d.d., dose-dependent; i.c.v., intracerebroventricular; i.p., intraperitoneal; NPY, neuropeptide Y; p.o., per oral; PP, pancreatic polypeptide; PVN, paraventricular nucleus; PYY, polypeptide YY Introduction One of the most potent inducers of feeding in mammals is neuropeptide Y (NPY), a 36 amino acid neurotransmitter. NPY is part of a family of structurally related peptides that also includes the hormones polypeptide YY (PYY) and pancreatic polypeptide (PP).
    [Show full text]
  • To Investigate the Physiological Role of Arcuate Nucleus Cocaine- and Amphetamine- Regulated Transcript in Energy Homeostasis
    To Investigate the Physiological Role of Arcuate Nucleus Cocaine- and Amphetamine- Regulated Transcript in Energy Homeostasis. Thesis submitted for the degree of Doctor of Philosophy in Imperial College London Daniel Charles Campbell 2010 Department of Investigative Medicine Faculty of Medicine Imperial College London 1 For my mum and dad, brothers and sisters 2 Abstract Cocaine- and amphetamine- regulated transcript (CART) was originally identified as a mRNA transcript upregulated in rats in response to administration of cocaine and amphetamine. CART is widely expressed in the central nervous system (CNS) with high levels of expression in hypothalamic nuclei such as the arcuate nucleus (ARC). CART was initially thought to act as an anorectic peptide since it is coexpressed with the anorectic neuropeptide pro-opiomelanocortin (POMC) in the ARC. In addition, intracerebroventricular (ICV) administration of CART (55-102) peptide inhibits feeding and administration of anti-CART antibody results in stimulation of feeding. However, subsequent studies have suggested CART may also act as an orexigen since injection of CART (55-102) specifically into the ARC and ventromedial nucleus (VMN) of the hypothalamus results in a significant increase in food intake. These data suggest CART acts through both anorectic and orexigenic circuits. Given the importance of the hypothalamus in the regulation of energy homeostasis, and the role of the ARC in integrating peripheral signals, it is essential to elucidate the role of ARC derived CART. In order to elucidate CART’s true physiological role in the ARC I used a combination of genetic approaches. I generated a recombinant Adeno-associated virus (rAAV) expressing CART antisense (CART-AS) and a transgenic mouse model which utilises the POMC promoter to drive expression of CART-AS.
    [Show full text]